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EP0646592A1 - Estradiol Derivat-Alkylierung Mittel Konjugate - Google Patents

Estradiol Derivat-Alkylierung Mittel Konjugate Download PDF

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Publication number
EP0646592A1
EP0646592A1 EP94307220A EP94307220A EP0646592A1 EP 0646592 A1 EP0646592 A1 EP 0646592A1 EP 94307220 A EP94307220 A EP 94307220A EP 94307220 A EP94307220 A EP 94307220A EP 0646592 A1 EP0646592 A1 EP 0646592A1
Authority
EP
European Patent Office
Prior art keywords
conjugate
derivative
formula
estradiol
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP94307220A
Other languages
English (en)
French (fr)
Inventor
Koichi Niimura
Takako Kawabe
Tsutomu Wada
Tsuyoshi Saitoh
Kenji Bannai
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kureha Corp
Original Assignee
Kureha Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kureha Corp filed Critical Kureha Corp
Publication of EP0646592A1 publication Critical patent/EP0646592A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • C07J1/0051—Estrane derivatives
    • C07J1/0066—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa
    • C07J1/007—Estrane derivatives substituted in position 17 beta not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
    • C07J1/0077—Ethers

Definitions

  • the present invention relates to a novel estradiol derivative-alkylating agent conjugate with reduced hormonal activity, a process for preparing the conjugate, compounds useful for the preparation of the conjugate, and a growth inhibiting composition containing the conjugate or estradiol derivative.
  • alkylating agents Although having a strong antitumor activity, there are many agents which fail to display their full medicinal effects. The primary reason is their limited dosage due to their undesirable side effects in medicinal use.
  • a solution to this problem is to combine the alkylating agent with a carrier having a specific affinity for the site of tumor to form an alkylating agent-carrier conjugate. It is intended to let the alkylating agent accumulate specifically at the site of tumor so that the agent will exhibit its antitumor activity effectively while suppressing the occurrence of the undesirable side effects.
  • an antitumor agent is usually required to be administered over a long period of time, so that even a slight side effect which is quite insignificant in short-term administration may give rise to a serious problem in long-time administration of the such agent. Especially, accumulation of the slight side effect may be remarkable as the physical strength of the cancer patient is usually weakened.
  • estradiol-chlorambucil conjugate in long-time administration thereof, there is observed in some cases development of the same symptoms as seen in administration of estrogen.
  • estradiol derivatives usable for the preparation of the conjugate are very low in estrogen action although they have a growth inhibiting activity. The present invention has been attained on the basis of these findings.
  • An object of the present invention is to provide a novel estradiol-alkylating agent conjugate which, while maintaining its original selective physiological activity, is reduced in estrogen action and of very high utility.
  • Another object of the present invention is to provide a process for preparing the conjugate, and estradiol derivatives useful for the preparation of the conjugate.
  • Still another object of the present invention is to provide a growth inhibiting agent containing the conjugate or the estradiol derivative, which agent is reduced in estrogen action.
  • a process for preparing the preferred conjugate which comprises reacting an estradiol derivative of the formula (II): wherein R1 is C1 ⁇ 4 alkyl or C1 ⁇ 4 alkoxy; R2 is acyl or benzyl; m is an integer of 1 to 3; n is an integer of 0 to 3; and X is hydroxy or halogen; with a compound of the formula (III): wherein R4 is carboxy, hydroxy or a salt thereof, halogen, ester group, acid chloride group, acid anhydride group or methyl halide group; and X is halogen or hydroxy.
  • a growth inhibiting composition containing an effective amount of the estradiol derivative-alkylating agent conjugate as defined in the first aspect, and a diluent.
  • a growth inhibiting composition containing an effective amount of an estradiol derivative of the formula (II): wherein R1 is C1 ⁇ 4 alkyl or C1 ⁇ 4 alkoxy; R2 is acyl or benzyl; m is an integer of 1 to 3; n is an integer of 0 to 3; and X is hydroxy or halogen, and a diluent.
  • the conjugate of the present invention has the structure represented by the formula (I).
  • R1 is preferably C1 ⁇ 4 alkyl or C1 ⁇ 4 alkoxy, more preferably methyl, and exists at the 1- or 4-position or at both of these positions.
  • R2 is benzoyl or benzyl.
  • m is 2 and n is an integer of 0 to 2. More preferably, n is 1 and R1 is methyl at the 1-position.
  • estradiol derivative moiety hydrogen of the hydroxy is substituted with acyl or benzyl.
  • Acyl may be C1 ⁇ 25 acyl, for instance, benzoyl, acetyl, palmitoyl, stearoyl, linoleoyl or the like. Of these groups, benzoyl is preferred.
  • the configuration at the 17-position of the estradiol derivative moiety may be ⁇ , ⁇ , or a mixture thereof, but ⁇ is preferred.
  • the alkylating agents usable in the present invention include chlorambucil, nitrogen mustard, melphalan and derivatives thereof including derivatives which have other halogen instead of chlorine.
  • the alkylating agent is chlorambucil and a derivative thereof which has other halogen instead of chlorine.
  • the alkylating agent is bound to an estradiol derivative at a site where the antitumor activity is not impaired by the binding. Binding between alkylating agent and estradiol-derivative may be effected through the medium of an appropriate spacer.
  • the preferred conjugate is represented by the formula (I): wherein R1, R2, m and n are as defined above, R3 is carbonyl or methylene, and X is hydroxy or halogen.
  • Halogen is usually chlorine, bromine or iodine.
  • the conjugate of the present invention may be prepared, for instance, according to the following process.
  • the compound of the formula (II) may be converted to a salt or halide thereof.
  • a halide can be obtained by treating a compound of the formula (II) wherein X is OH, with p-toluenesulfonyl chloride and sodium halide or the like.
  • a salt can be obtained by the conventional method.
  • R1 is C1 ⁇ 2 alkyl or C1 ⁇ 2 alkoxy
  • R2 is benzoyl or benzyl
  • m is 2
  • n is an integer of 0 to 2.
  • R1 is methyl and exists at the 1- and/or 4-position, especially at the 1-position.
  • estradiol derivative is combined with the desired alkylating agent.
  • the estradiol derivative of the formula (II) is reacted with a compound of the formula (III): where R4 is carboxy, hydroxy or a salt thereof, halogen, ester group, acid chloride group, acid anhydride group or methyl halide group; and X is halogen or hydroxy, to form a conjugate of the formula (I).
  • the reaction can be carried out in an organic solvent such as dichloromethane, dioxane, dimethyl sulfoxide, dimethylformamide, pyridine, benzene, acetone, toluene, carbon tetrachloride, chloroform, tetrahydrofuran or the like.
  • An alkali solution, sodium hydride, thionyl chloride and the like may be added as desired.
  • the reaction may be performed at -30 to 150°C, preferably -10 to 100°C, for 3 minutes to 48 hours, preferably 5 minutes to 24 hours.
  • the reaction product is purified by a usual method to give the conjugate of the present invention.
  • the conjugate of the formula (I) in which the 3-position of the estradiol is benzyloxy is debenzylated by treating it with Pd/C in the presence of H2 and then further reacted with an acid chloride or acid anhydride corresponding to the objective acyl to provide the conjugate of the present invention in which the 3-position of the estradiol is acyloxy.
  • the conjugate of the formula (I) and the estradiol derivatives of the formula (II) are excessively weakened in estrogen action and low in toxicity and also have a growth inhibiting action, so that they are useful as a growth inhibiting agent.
  • the substances also show a growth inhibiting action against tumor cells, so that they can be applied as an antitumor agent. They are effective against various types of cancers such as breast cancer, ovarian cancer, uterine cancer, prostatic cancer, stomach cancer, rectal cancer, colonic cancer, renal cancer, cancer of hematopoietic organ, liver cancer, cancer of urinary organ, and other solid cancers.
  • the conjugate and the estradiol derivative also have an inhibiting action against prostatic hypertrophy and are therefore useful as an anti-prostatic hypertrophy agent.
  • the conjugate and the estradiol derivative for use of the conjugate and the estradiol derivative as a growth inhibiting agent, it can be prepared into various forms suited for the ways of administration in combination with a diluent (carrier) according to the known methods.
  • a pharmaceutically acceptable diluent is used.
  • the forms of composition include capsule, syrup, oral preparations such as pills and tablets, injections, external preparations, suppository, etc.
  • the external preparations include solid agents containing a percutaneous penetration auxiliary such as lauric acid diethanol amide in an ordinary base such as white vaseline.
  • the conjugate and the estradiol derivative each may be contained in an amount of preferably 0.01 to 75% by weight, more preferably 0.05 to 25% by weight.
  • the conjugate and the estradiol derivative can be administered through various routes such as peroral, percutaneous, intramuscular, intravenous, intraarterial, intrarectal, etc.
  • the dosage is variable depending on the way of administration and the degree of treatment, but generally it is 0.1 to 50 mg/kg per day in the case of peroral administration and 0.01 to 20 mg/kg per day in the case of parenteral administration, both for adults.
  • the estradiol derivative moiety in the conjugate of the present invention has an ether linkage at the 17-position in addition to a substitutent at the 3-position of the A ring. This structure is considered to lend itself to excessive diminution of the estrogen action while allowing maintenance of the growth inhibiting action which is inherently possessed by the estradiol-alkylating agent conjugate, thus remarkably enhancing the utility of the conjugate as a growth inhibiting agent.
  • Benzene was added to 3-benzyloxy-1,3,5(10)-estratriene-17-one (V-1) (0.11 g), ethylene glycol (0.23 g) and p-toluenesulfonic acid (0.6 mg). This mixture was azeotropically boiled at 120°C by a Dean-Stark apparatus and stirred overnight. An excess amount of triethylamine was added to the reaction solution to neutralize, and the mixed solution was concentrated under reduced pressure and extracted with ethyl acetate (50 ml). The organic layer was washed with distilled water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to produce the crystals (0.14 g).
  • This solution was treated with H2 gas at room temperature for 5 hours to obtain a debenzylated compound (1.77 g).
  • This compound was dissolved in dry dichloromethane (30 ml), followed by addition of pyridine (8.5 ml) and benzoyl chloride (596.0 ml), and the mixed solution was stirred overnight at room temperature.
  • the stirred solution was distilled and the residue was dissolved in ethyl acetate (60 ml), washed twice with water (20 ml) and further washed with a saturated saline solution (20 ml). The washings were distilled and the residue was crystallized.
  • the crystallized product was filtered out, collected and washed with hexane (3 ml) to produce a benzoyl compound (1.53 g).
  • This compound was dissolved in ethanol (85 ml) and PPTS (1.24 g), and the solution was stirred at 40°C for 2 hours and distilled.
  • the residue was dissolved in ethyl acetate (100 ml) and washed with water (30 ml) and a hydrochloric acid solution (1N, 30 ml).
  • the organic layer was dried over Na2SO4, filtered and distilled.
  • the residue was crystallized, again dissolved in ethyl acetate/hexane (1:3) (50 ml) and recrystallized.
  • This reaction mixture was filtered through filter paper while washing with 1,4-dioxane, and the filtrate was concentrated under reduced pressure to produce an oily substance (92.7 mg).
  • This oily substance was dissolved in dichloromethane (0.5 ml), followed by addition of pyridine (0.3 ml) and benzoyl chloride (0.02 ml) at 0°C, and stirred overnight at room temperature.
  • the reaction solution was extracted with ethyl acetate (50 ml) and the extract was washed with a saturated saline solution. The washings were dried over anhydrous sodium sulfate and concentrated under reduced pressure to produce an oily substance (116.7 mg).
  • the compounds of the present invention dissolved in sesame oil (containing 3% benzyl alcohol) were each administered once intraperitoneally to 6-week-old ICR female mice (average body weight: 25 g) at a dosage of 100 mg/kg.
  • the test mice were observed for a period of 7 days after administration of the compounds. No death was observed in any case of the compounds.
  • test compounds and estradiol dissolved in sesame oil were each administered once hypodermically to 3-week-old Wistar female rats. 24 hours later, the uterus of each test rat was removed and its weight (ratio to the body weight) was measured. From the relation between the uterus weight/body weight ratio and the dosage, the compound dosage that gives a uterus weight/body weight ratio twice that in the control group was determined. The dosages of the test compounds are shown as a ratio to the dosage of estradiol.
  • the SC-115 cells were cultured on a 96-well microplate (5,000 cells/well) for 24 hours with a culture medium (200 ⁇ l/well; Ham's F-12/MEM-E (98%), dextran-treated fetal calf serum (2%) and testosterone (1 ⁇ 10 ⁇ 8 M)).
  • the culture medium was replaced with fresh medium containing the test compound (Ham's F-12/MEM-E, bovine serum albumin (0.1%), testosterone (1 ⁇ 10 ⁇ 8 M) and test compound of various concentrations).
  • the culture medium was replaced every two days, and culture was continued for 7 days. Thymidine (1 ⁇ ci/ml, tritium-labeled) was added, and 5 hours later, the culture medium was removed.
  • the DU-145 cells were cultured on a 96-well microplate (5,000 cells/well) for 24 hours with a culture medium (200 ⁇ l/well; Ham's F-12/MEM-E (98%) and dextran-treated fetal calf serum (2%)). Then the culture medium was replaced with fresh medium containing the test compound (Ham's F-12/MEM-E, bovine serum albumin (0.1%), bovine pituitary-derived bFGF (1 ng/ml) and the test compound of various concentrations). Culture with this medium was continued for 4 days. Thymidine (1 ⁇ ci/ml, tritium-labeled) was added, and 5 hours layer, the culture medium was removed.
  • a culture medium 200 ⁇ l/well; Ham's F-12/MEM-E (98%) and dextran-treated fetal calf serum (2%). Then the culture medium was replaced with fresh medium containing the test compound (Ham's F-12/MEM-E, bovine serum albumin
  • the cells were washed with PBS and then washed twice with ice-cold trichloroacetic acid (10%). Then the cells were dissolved in 0.5N sodium hydroxide and neutralized with 0.5N hydrochloric acid. The radioactivity of the neutralized solution was measured by a liquid scintillation counter to determine the growth inhibiting effect (IC50). The results are shown in Table 3.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP94307220A 1993-10-05 1994-10-03 Estradiol Derivat-Alkylierung Mittel Konjugate Withdrawn EP0646592A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP5273014A JPH07101977A (ja) 1993-10-05 1993-10-05 ホルモン作用を軽減した新規なエストラジオール誘導体及びその増殖因子阻害剤
JP273014/93 1993-10-05

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EP0646592A1 true EP0646592A1 (de) 1995-04-05

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EP94307220A Withdrawn EP0646592A1 (de) 1993-10-05 1994-10-03 Estradiol Derivat-Alkylierung Mittel Konjugate

Country Status (6)

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US (5) US5478818A (de)
EP (1) EP0646592A1 (de)
JP (1) JPH07101977A (de)
KR (1) KR950011462A (de)
AU (1) AU664809B2 (de)
CA (1) CA2133281A1 (de)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004041839A3 (en) * 2002-11-08 2004-07-01 Pantarhei Bioscience Bv Synthesis of estetrol via estrone derived steroids
US10844088B2 (en) 2011-07-19 2020-11-24 Estetra Sprl Process for the preparation of estetrol
US10888518B2 (en) 2015-06-18 2021-01-12 Estetra Sprl Orodispersible tablet containing estetrol
US10894014B2 (en) 2015-06-18 2021-01-19 Estetra Sprl Orodispersible tablet containing Estetrol
US11053273B2 (en) 2011-06-01 2021-07-06 Estetra S.P.R.L. Process for the production of estetrol intermediates
US11053274B2 (en) 2011-06-01 2021-07-06 Estetra S.P.R.L. Process for the production of estetrol intermediates
US11147771B2 (en) 2015-06-18 2021-10-19 Estetra Sprl Orodispersible dosage unit containing an estetrol component
US11452733B2 (en) 2018-04-19 2022-09-27 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US11484539B2 (en) 2018-04-19 2022-11-01 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US11896602B2 (en) 2016-08-05 2024-02-13 Estetra Srl Method for preventing pregnancy
US11957694B2 (en) 2015-06-18 2024-04-16 Estetra Srl Orodispersible dosage unit containing an estetrol component

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US6054446A (en) * 1997-12-24 2000-04-25 Sri International Anti-estrogenic steroids, and associated pharmaceutical compositions and methods of use
JP3551870B2 (ja) 1999-11-24 2004-08-11 日本電気株式会社 Ｖｄｔ障害緩和装置／方法およびｖｄｔ障害危険性定量化装置／方法ならびに記録媒体
KR20080034440A (ko) * 2005-06-28 2008-04-21 스미또모 가가꾸 가부시끼가이샤 과산화물 분해 촉매
US8006042B2 (en) * 2007-11-26 2011-08-23 Globalfoundries Inc. Floating point bypass retry
RU2422915C1 (ru) * 2010-02-12 2011-06-27 Юрий Николаевич Бордюшков Способ торможения пролиферативного процесса в ткани предстательной железы в эксперименте

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Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10000524B2 (en) 2002-11-08 2018-06-19 Donesta Bioscience B.V. Synthesis of estetrol via estrone derived steroids
WO2004041839A3 (en) * 2002-11-08 2004-07-01 Pantarhei Bioscience Bv Synthesis of estetrol via estrone derived steroids
US11053273B2 (en) 2011-06-01 2021-07-06 Estetra S.P.R.L. Process for the production of estetrol intermediates
US11053274B2 (en) 2011-06-01 2021-07-06 Estetra S.P.R.L. Process for the production of estetrol intermediates
US10844088B2 (en) 2011-07-19 2020-11-24 Estetra Sprl Process for the preparation of estetrol
US10888518B2 (en) 2015-06-18 2021-01-12 Estetra Sprl Orodispersible tablet containing estetrol
US10894014B2 (en) 2015-06-18 2021-01-19 Estetra Sprl Orodispersible tablet containing Estetrol
US11147771B2 (en) 2015-06-18 2021-10-19 Estetra Sprl Orodispersible dosage unit containing an estetrol component
US11793760B2 (en) 2015-06-18 2023-10-24 Estetra Srl Orodispersible dosage unit containing an estetrol component
US11957694B2 (en) 2015-06-18 2024-04-16 Estetra Srl Orodispersible dosage unit containing an estetrol component
US11964055B2 (en) 2015-06-18 2024-04-23 Estetra Srl Orodispersible dosage unit containing an estetrol component
US11896602B2 (en) 2016-08-05 2024-02-13 Estetra Srl Method for preventing pregnancy
US11452733B2 (en) 2018-04-19 2022-09-27 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US11484539B2 (en) 2018-04-19 2022-11-01 Estetra Sprl Compounds and their uses for alleviating menopause-associated symptoms
US11666585B2 (en) 2018-04-19 2023-06-06 Estetra Srl Compounds and their uses for alleviating menopause-associated symptoms

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US5480878A (en) 1996-01-02
CA2133281A1 (en) 1995-04-06
US5561125A (en) 1996-10-01
US5491138A (en) 1996-02-13
US5633393A (en) 1997-05-27
AU7423194A (en) 1995-04-27
US5478818A (en) 1995-12-26
AU664809B2 (en) 1995-11-30
JPH07101977A (ja) 1995-04-18
KR950011462A (ko) 1995-05-15

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